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      SARS-CoV-2 Placentitis and Intraparenchymal Thrombohematomas Among COVID-19 Infections in Pregnancy


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          This cases series examines SARS-CoV-2 placentitis and intraparenchymal thrombohematomas among COVID-19 infections during pregnancy.

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          Risk for Stillbirth Among Women With and Without COVID-19 at Delivery Hospitalization — United States, March 2020–September 2021

          Pregnant women are at increased risk for severe COVID-19–related illness, and COVID-19 is associated with an increased risk for adverse pregnancy outcomes and maternal and neonatal complications ( 1 – 3 ). To date, studies assessing whether COVID-19 during pregnancy is associated with increased risk for stillbirth have yielded mixed results ( 2 – 4 ). Since the B.1.617.2 (Delta) variant of SARS-CoV-2 (the virus that causes COVID-19) became the predominant circulating variant,* there have been anecdotal reports of increasing rates of stillbirths in women with COVID-19. † CDC used the Premier Healthcare Database Special COVID-19 Release (PHD-SR), a large hospital-based administrative database, § to assess whether a maternal COVID-19 diagnosis documented at delivery hospitalization was associated with stillbirth during March 2020–September 2021 as well as before and during the period of Delta variant predominance in the United States (March 2020–June 2021 and July–September 2021, respectively). Among 1,249,634 deliveries during March 2020–September 2021, stillbirths were rare (8,154; 0.65%): 273 (1.26%) occurred among 21,653 deliveries to women with COVID-19 documented at the delivery hospitalization, and 7,881 (0.64%) occurred among 1,227,981 deliveries without COVID-19. The adjusted risk for stillbirth was higher in deliveries with COVID-19 compared with deliveries without COVID-19 during March 2020–September 2021 (adjusted relative risk [aRR] = 1.90; 95% CI = 1.69–2.15), including during the pre-Delta (aRR = 1.47; 95% CI = 1.27–1.71) and Delta periods (aRR = 4.04; 95% CI = 3.28–4.97). COVID-19 documented at delivery was associated with increased risk for stillbirth, with a stronger association during the period of Delta variant predominance. Implementing evidence-based COVID-19 prevention strategies, including vaccination before or during pregnancy, is critical to reducing the impact of COVID-19 on stillbirths. Delivery hospitalizations were identified from PHD-SR using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnostic and procedure codes pertaining to obstetric delivery and diagnosis-related group delivery codes. ¶ Deliveries with discharge dates during March 2020–September 2021 were included. Stillbirths, defined as fetal deaths at ≥20 weeks’ gestation, were identified using maternal ICD-10-CM diagnosis codes.** Hospitalizations without ICD-10-CM codes indicating gestational age or with ICD-10-CM codes indicating gestational age 90% of U.S. COVID-19 cases during July–September 2021.¶¶¶¶ Sixth, it was not possible to assess vaccination status in this analysis. However, because COVID-19 vaccines are highly effective,***** and COVID-19 vaccination coverage among pregnant women was approximately 30% as of July 2021,††††† most women with COVID-19 at delivery were likely unvaccinated. Finally, although the PHD-SR included a large population across U.S. Census divisions, it represents delivery hospitalizations from a convenience sample of reporting hospitals, limiting generalizability of results to the U.S. population. This analysis adds to growing evidence of an association between COVID-19 in pregnancy and stillbirth, highlights that the risk for stillbirth associated with COVID-19 is affected by maternal morbidity, and demonstrates that the risk has increased during the Delta period. Further investigation from prospective studies is warranted to confirm these findings, identify the biologic mechanism for the observed increased risk for stillbirth with maternal COVID-19, and assess differences in risks relative to the timing and severity of infection and the contribution of maternal risk factors. In addition, further investigation of vaccine effectiveness during pregnancy, including prevention of stillbirth, is warranted. Most importantly, these findings underscore the importance of COVID-19 prevention strategies, including vaccination before or during pregnancy. Summary What is already known about this topic? Pregnant women are at increased risk for severe disease from COVID-19, and COVID-19 is associated with an increased risk for adverse perinatal outcomes. What is added by this report? Among 1,249,634 delivery hospitalizations during March 2020–September 2021, U.S. women with COVID-19 were at increased risk for stillbirth compared with women without COVID-19 (adjusted relative risk [aRR] = 1.90; 95% CI = 1.69–2.15). The magnitude of association was higher during the period of SARS-CoV-2 B.1.617.2 (Delta) variant predominance than during the pre-Delta period. What are the implications for public health practice? Implementing evidence-based COVID-19 prevention strategies, including vaccination before or during pregnancy, is critical to reduce the impact of COVID-19 on stillbirths.
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            Defining Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Placentitis

            Context.— Case reports and rare case series have demonstrated variable placental pathology in the setting of maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In rare small studies demonstrating infection of the placental parenchyma, histologic manifestations have included variable degrees of histiocytic intervillositis, perivillous fibrin deposition, and syncytiotrophoblast necrosis. Objective.— To characterize the placental pathologic features of SARS-CoV-2–infected placentas, irrespective of fetal-maternal transmission, and to examine the frequency of C4d activation in such cases. Design.— A retrospective study of 7 placentas from mothers with active SARS-CoV-2 infection and placental infection as demonstrated by RNA in situ hybridization was conducted. Results.— There were 6 placentas from live-born neonates (5 singletons, 1 nonfused diamniotic-dichorionic twin placenta), and 1 was from a stillbirth. A total of 5 of the 8 neonates (including the stillbirth) tested negative for SARS-CoV-2, and all were negative for neonatal infection. The remaining 3 neonates were well at time of discharge. All placentas were positive for SARS-CoV-2 infection by RNA in situ hybridization and demonstrated variable degrees of histiocytic intervillositis, perivillous fibrin deposition, and trophoblast necrosis. Three cases demonstrated features of fetal vascular malperfusion. CD68 highlighted intervillous histiocytes. C4d expression was present along the villous borders in 6 of 7 cases. Conclusions.— SARS-CoV-2 placentitis is defined by the triad of histiocytic intervillositis, perivillous fibrin deposition, and trophoblast necrosis. The features may occur in cases without confirmed transplacental transmission. The damage caused by SARS-CoV-2 placentitis is likely mediated by complement activation.
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              Placental Tissue Destruction and Insufficiency from COVID-19 Causes Stillbirth and Neonatal Death from Hypoxic-Ischemic Injury: A Study of 68 Cases with SARS-CoV-2 Placentitis from 12 Countries

              Perinatal death is an increasingly important problem as the COVID-19 pandemic continues, but the mechanism of death has been unclear. To evaluate the role of the placenta in causing stillbirth and neonatal death following maternal infection with COVID-19 and confirmed placental positivity for SARS-CoV-2. Case-based retrospective clinico-pathological analysis by a multinational group of 44 perinatal specialists from 12 countries of placental and autopsy pathology findings from 64 stillborns and 4 neonatal deaths having placentas testing positive for SARS-CoV-2 following delivery to mothers with COVID-19. All 68 placentas had increased fibrin deposition and villous trophoblast necrosis and 66 had chronic histiocytic intervillositis, the three findings constituting SARS-CoV-2 placentitis. Sixty-three placentas had massive perivillous fibrin deposition. Severe destructive placental disease from SARS-CoV-2 placentitis averaged 77.7% tissue involvement. Other findings included multiple intervillous thrombi (37%; 25/68) and chronic villitis (32%; 22/68). The majority (19, 63%) of the 30 autopsies revealed no significant fetal abnormalities except for intrauterine hypoxia and asphyxia. Among all 68 cases, SARS-CoV-2 was detected from a body specimen in 16 of 28 cases tested, most frequently from nasopharyngeal swabs. Four autopsied stillborns had SARS-CoV-2 identified in internal organs. The pathology abnormalities composing SARS-CoV-2 placentitis cause widespread and severe placental destruction resulting in placental malperfusion and insufficiency. In these cases, intrauterine and perinatal death likely results directly from placental insufficiency and fetal hypoxic-ischemic injury. There was no evidence that SARS-CoV-2 involvement of the fetus had a role in causing these deaths.

                Author and article information

                JAMA Netw Open
                JAMA Netw Open
                JAMA Network Open
                American Medical Association
                21 March 2022
                March 2022
                21 March 2022
                : 5
                : 3
                [1 ]Department of Pathology, Massachusetts General Hospital, Boston
                [2 ]Department of Pathology, St Louis University School of Medicine, St Louis, Missouri
                [3 ]Division of Maternal Fetal Medicine, Department of Obstetrics & Gynecology, Massachusetts General Hospital, Boston
                [4 ]Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio
                Author notes
                Article Information
                Accepted for Publication: February 13, 2022.
                Published: March 21, 2022. doi:10.1001/jamanetworkopen.2022.5345
                Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Huynh A et al. JAMA Network Open.
                Corresponding Author: Drucilla J. Roberts, MD, MS, Department of Pathology, Massachusetts General Hospital, 55 Fruit St, WRN219, Boston, MA 02114 ( djroberts@ 123456mgh.harvard.edu ).
                Author Contributions: Drs Huynh and Roberts had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Huynh and Sehn contributed equally.
                Concept and design: Huynh, Sehn, Goldfarb, Watkins, Roberts.
                Acquisition, analysis, or interpretation of data: All authors.
                Drafting of the manuscript: Huynh, Sehn, Watkins, Roberts.
                Critical revision of the manuscript for important intellectual content: Sehn, Goldfarb, Watkins, Torous, Heerema-McKenney, Roberts.
                Statistical analysis: Huynh.
                Administrative, technical, or material support: Goldfarb.
                Supervision: Torous, Roberts.
                Conflict of Interest Disclosures: Dr Heerema-McKenney reported receiving personal fees from Elsevier and from UpToDate outside the submitted work. Dr Roberts reported being an author for Cambridge University Press and UpToDate on perinatal pathology topics for which she receives royalties outside the submitted work. No other disclosures were reported.
                Additional Contributions: David Ting, MD, and Jonathan Li, MD, performed technical work on strain identification in selected cases. Andrea Edlow, MD, and Lydia Shook, MD, assisted in research. Amelia Sybenga, DO; Sandy Wu, MD; Melissa Kahn, MD; Carolyn K. B. Wall, MD; Laura O. Rabinowitz, MD; Michael Wilson, MD; Kavitha Rao, MD; Maria A. Aguiar, MD; Denis M. McCarthy, MD; Matthew R. Simmons, MD; Jaya Asirvatham, MD; David Gray, MD; Deirdre Knobeloch, MD; Megha Joshi, MD; Robert Najarian, MD; Nicole Esposito, MD; Bradley Quade, MD, PhD; Emily Meserve, MD; Kimberly Heightchew, MD; Melissa Ann Hanek Gener, MD; and Lisa Shane, MD, contributed cases with clinical and pathological information. Javier Mendez-Pena contributed immunohistochemistry and RNA-ISH studies. William Anim and his team contributed histology preparation. Linda Arini contributed administrative assistance. They were not compensated for their contributions.
                Copyright 2022 Huynh A et al. JAMA Network Open.

                This is an open access article distributed under the terms of the CC-BY License.

                Research Letter
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                Infectious Diseases


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